Recent studies of the human genome have revealed large blocks of almost identical sequences in particular chromosomal regions, comprising about 5 percent of the human genomic sequence. Non-allelic homologous recombination between these paralogous sequences results in changes of genomic structure creating inversions and other types of chromosomal rearrangements. Variation in chromosomal architecture, such as submicroscopical inversions, is more widespread in the human genome than previously thought. One example of a common inversion polymorphism is identified on chromosome 8p23. The main goal of this proposal is to characterize the 8p23 inversion region and develop tools for genome-wide investigation of similar rearrangements. The 8p23 rearrangement, an inversion polymorphism spanning about a 4Mb region flanked by paralogous sequences, was only recently recognized on different haptotypes. The region surrounding or including the inversion on chromosome 8p has been implicated by several independent mapping studies of complex phenotypes including schizophrenia, bipolar disorder, Tourette syndrome, harm avoidance, and prostate cancer susceptibility. Understanding the underlying structure and history of the 8p inversion region is needed to study its role in genome evolution and investigation of these putative loci also requires molecular characterization of the 8p inversion region. Little is known about common inversions. We will conduct detailed analysis of the flanking paralogous sequences and investigate the presence of haplotypes blocks for this region; this will reveal the phylogenetic history of these duplicated segments and enable us to reconstruct the most likely ancestral configuration. Expression profiles will be established for different inversion haplotypes to test the hypothesis that 8p inversion events may affect local or more global gene expression. We will develop a simple assay in order to screen large numbers of samples for the presence of the 8p inversion. Additionally, this and similar inversions may affect the results of statistical genetic analyses; we will investigate the possible implications of these rearrangements on mapping studies, develop statistical methods for linkage and linkage disequilibrium mapping to integrate inversion information for each chromosome, and re-analyze prior genotype data for the different traits that were previously associated with this region. Furthermore, tools will be developed and applied to predict and identify additional genome regions with similar variability, further expanding the possible link between chromosomal architecture and complex traits.